This project proposes a set of studies of the neurobiology of major depression and the mechanism of action of somatic antidepressants through PET quantitative imaging of serotonin receptors. A reduction in the number of serotonin transporter sites (SERT) has been observed in postmortem brain and platelet binding studies. Reduced SERT binding may indicate reduced serotonin innervation of key brain regions. One of the most promising theories explaining the delayed action of antidepressant medications in enhancing serotonergic release is based on animal studies using electrophysiological, in vivo microdialysis and autoradiographic receptor binding techniques. These studies have found that many diverse antidepressant medications produce a delayed desensitization of somatodendritic 5HT1A autoreceptors that enhances serotenergic transmission. These observations can now be tested in the human brain. We therefore propose to test these hypotheses directly in vivo using PET and the ligands [11C]MvN5652 to image the SERT, and [11C]Way-100635 to image the 5-HT1A receptor in healthy volunteers, medication-free patients with major depression, and patients with major depression after the initiation of treatment with antidepressants.